The glucocorticoid receptor (GR) is a steroid hormone receptor that serves as a transcriptional regulator in the human stress response when bound to its ligand, cortisol. A study of gastric carcinomas found that the GR promoter was methylated in 20-30% of cases, which was three times higher than in normal gastric tissue (Kang, et al. (2008) Laboratory Investigation; a Journal of Technical Methods and Pathology 88:161-70). Small cell lung carcinoma (SCLC) cell lines also exhibited increased promoter methylation (Kay, et al. (2011) PloS One 6:e24839). In addition, the GR gene was methylated in 25% of colorectal carcinomas and 35% of colorectal cancer cell lines, and methylation was associated with a decrease in gene expression (Lind, et al. (2006) Cell. Oncol. 28:259-272). However, methylated GR gene was not detected in ovarian cancer (Wu, et al. (2007) Mol. Cancer 6:45).
In breast cancer, GR protein expression has been disclosed to decrease significantly with tumor histologic grade, with one study reporting expression reduced below 50% that of normal tissue (Lien, et al. (2006) J. Pathol. 209:317-27). Investigation of estrogen receptor (ER)-negative and progesterone receptor (PR)-negative tissues has also shown that all were negative for GR, suggesting that GR loss may occur early during breast tumorigenesis (Buxant, et al. (2010) Appl. Immunohist. Mol. Morph. 18:254-7).
The human GR gene (NR3C1) spans 80 kbp on chromosome 5 and contains 8 coding exons (2-9) and nine tissue-specific alternative first exons (Turner, et al. (2005) J. Mol. Endocrinol. 35:283-92) located in two distinct promoter regions: the distal promoter approximately 30 kbp upstream of the translation start site and the proximal promoter located in a 3 kbp CpG island 5 kbp upstream from the ATG start codon (Turner, et al. (2010) Biochem. Pharmacol. 80:1860-8; Breslin, et al. (2001) Mol. Endocrinol. 15:1381-95). Cloning of the intronic regions between the alternative first exons into luciferase reporters has shown that each alternative first exon has its own unique promoter, and methylation of these promoters by SssI methyltransferase successfully reduced activity to below 10%, indicating that individual first exon promoters are susceptible to epigenetic control (Cao-Lei, et al. (2011) Human Genet. 129:533-43). It has also been suggested that methylation of these promoters may be subject to individualized, highly variable regulation (Turner, et al. (2008) Nucl. Acids Res. 36:7207-18). A previous study investigating GR promoter methylation in breast cancer disclosed no detectable methylation (Lien, et al. (2006) supra).
A role for unliganded GR as a positive regulator of BRCA1 activity has been disclosed (Ritter, et al. (2012) Mol. Cancer Res. 10(4):558-69). BRCA1 is an important gene in breast cancer etiology as its protein product is involved in cell regulatory processes including DNA repair (Birgisdottir, et al. (2006) Breast Cancer Res. 8:R38).